It has recently become clear that interferon (IFN) mediates a variety of immunoregulatory effects both in vivo and in vitro. Evidence from many experimental systems suggests that the natural killer (NK) cell-IFN system may play an important role in host defenses against malignant disease and virus infection. This project involves a study of immunoregulatory mechanisms in human cancer, with particular emphasis on the role of IFN. We have recently described deficient NK activity in patients with advanced cancer, despite an apparently normal number of functionally active NK cells and normal production of IFN. The nature of this defect is unclear at present. In addition, we have found an apparent decreased sensitivity of PBL from advanced cancer patients to the immunoregulatory effects of IFN in vitro. The specific objectives of this research project are as follows: (1)\To further delineate the defect in NK activity in patients with cancer through kinetic studies on recycling of NK cells, measurement of soluble cytotoxic factor produced by NK cells and use of specific monoclonal antibodies to enumerate NK cells; (2)\To compare the immunoregulatory effects of different IFNs and IFN inducers on T-cell function and NK activity of PBL from normal donors and cancer patients; (3)\To study NK activity and IFN production in patients at risk of developing cancer and in patients with papilloma virus-induced tumors; (4)\To examine the mechanism of IFN-induced suppression of T-cell responses to mitogen including delineation of the effector and target cells involved and their surface markers; use of monoclonal antibodies to delineate lymphocyte subsets responsible for the production of the different IFNs and for suppression induced by Con A, viruses and tumor cells.